Recently, researchers and clinicians have focused increased attention on a group of children with severe mood and behavioral dysregulation (SMD). These children are characterized by impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. Because this syndrome shares many clinical features with bipolar disorder (BD), there is considerable debate as to whether these children should be diagnosed with BD. However, children with this syndrome do not exhibit the distinct manic episodes required for the diaongsis of BD. Furthermore, other DSM-IV diagnoses (ADHD, ODD, etc.) capture heterogeneous clinical populations that include many children who do not exhibit the symptoms noted above. Therefore, the goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally, and follow them longitudinally, 2) to compare the brain function of SMD children (assessed with functional MRI and standardized behvioral testing)to that of children with unequivocal BPD; 3) to conduct a double-blinded, placebo-controlled trial of lithium in children with SMD. Standardized interview modules and rating scales will be used to rate the clinical features of mood dysregulation. A double-blind, placebo-controlled trial of lithium will be conducted, and magnetic resonance spectroscopy (MRS) will be preformed before and after treatment to ascertain effects of lithium treatment on brain metabolites. Data from standardized behavioral paradigms have been obtained on approximately 100 children with SMD and matched controls in order to identify deficits in core psychological processes associated with the disorder. In addition, functional MRI data have been obtained on approximately 40 SMD children on paradigms that have also been used in children with BPD and ADHD. The fMRI data are currently being analyzed. The behavioral adata show that children with SMD have face emotion labeling deficits that are similar to those of children with BD. Children with SMD, but not those with BD, have deficits in their responses to punishing stimuli. While both youth with SMD and those with BD have deficits in response flexibility (i.e., their ability to adapt to tasks in which choosing first one, and then another, stimulus is rewarded), the deficits of the SMD youth are not as consistent as those of the BD youth. Data also indicate that children with SMD differ from those with BPD in their psychophysiological and behavioral responses to frustration, although the affective responses of the two patient groups are similar. In addition, data indicate that youth with BD are more likely to have parents with BD than are youth with SMD. A post-hoc analysis of data from two longitudinal epidemiological studies indicate that children with SMD or severe, chronic impairing irritability are more likely than non-SMD children to meet criteria for depression, but not BPD, in early adulthood. In sum, these data indicate that there are significant differences between SMD and BD youth in terms of clinical course, family history, and brain mechanisms mediating symptoms, although there are also some deficits shared in common (e.g. errors in face emotion processing). Taken together, these data indicate that SMD should not be assumed to be a developmental presentation of BD, although the two clinical syndromes may ultimately be found to share some pathophysiological mechanisms. Finally, approximately 15 patients have completed the treatment trial, and MRS scans have been obtained.